Synthesis and crystallization of piperazine ring-containing compounds

ABSTRACT

The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130° C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2′-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-methylpiperazine to form mirtazapine. The present invention also relates to new processes for recrystallization of mirtazapine from crude mirtazapine.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 09/552,485, filedApr. 18, 2000, which claims the benefit of U.S. Provisional ApplicationNo. 60/130,047, filed Apr. 19, 1999.

FIELD OF THE INVENTION

The present invention relates to synthetic organic chemistry,particularly, to synthesis of piperazine ring-containing compounds, suchas mirtazapine, and to the crystallization of mirtazapine from differentsolvents and solvent systems.

BACKGROUND OF THE INVENTION

Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2] benzazepine, having the formula I:

is approved, under the trademark Remeron®, by the U.S. Food and DrugAdministration, for the treatment of depression. Mirtazapine has atetracyclic chemical structure unrelated to other classes ofantidepressants such as selective serotonin reuptake inhibitors,tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to thepiperazinoazepine group of compounds.

Mirtazapine may be made by methods described in U.S. Pat. No. 4,062,848.By a process of U.S. Pat. No. 4,062,848 (“the '848 patent”), themirtazapine intermediate1-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by athree step process starting with a 2,3-substituted pyridine derivative.Therefore, as shown in Scheme 1, when starting with2-amino-3-cyano-pyridine, the process of the '848 patent requires foursynthetic steps to make mirtazapine. It is desirable to have a processfor making mirtazapine that requires fewer steps, and therefore requiresless reagent, solvent and time.

By the process of U.S. Pat. No. 4,062,848 (“the 848 patent”), themirtazapine intermediate1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by thehydrolysis of the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine under highly basicconditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile,at high temperature and for long reaction times of 24 hours. These harshreaction conditions necessitate a great effort in purifying theresulting product as well as creating environmental waste disposalissues associated with neutralizing and disposing of large volumes ofconcentrated basic solutions. The highly basic conditions and longreaction times make the procedure of the '848 patent very costly,especially in terms of reactor time.

According to the methods of U.S. Pat. No. 4,062,848, crude mirtazapineis recrystallized only in ether and petrol ether 40-60. The solventsether and petrol ether 40-60 are both very difficult to handle in largescale production.

SUMMARY OF THE INVENTION

The present invention is directed to a method for the preparation ofmirtazapine, comprising the steps of: reacting a compound of the formula

with a compound of the formula

to form a compound of the formula

adding a ring closing reagent to the compound of the formula

to form mirtazapine, wherein R¹ is selected from the group consisting ofhydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R² is amine;and R³ is selected from the group consisting of chloro, fluoro, bromoand iodo.

In a preferred embodiment of the present invention is directed to amethod for the preparation of mirtazapine, comprising the steps ofreacting 2-amino-3-hydroxymethyl pyridine withN-methyl-1-phenyl-2,2′-iminodiethyl chloride to form1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and addingsulfuric acid to the1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to formmirtazapine.

Further, it has now been discovered that the mirtazapine intermediate1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made byhydrolysis of the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new morefavorable reaction conditions. The new reaction conditions of thepresent invention include a low mole to mole ratio of potassiumhydroxide to nitrile and shorter reaction times.

The present invention relates to a improved process for making1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the step ofreacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a basewherein the base is present in a ratio of up to about 12 moles of thebase per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.

In a preferred embodiment of the present invention, the ratio of thebase to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12moles of base to about one mole of1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles ofbase to about one mole of1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.

In another preferred embodiment of the present invention, the base ispotassium hydroxide or sodium hydroxide.

In another embodiment of the present invention, the mixture of the1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heatedto at least about 130° C.

In another embodiment of the present invention, the hydrolysis of1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in amixture water and a solvent selected from the group consisting ofmethanol, ethanol, propanol, isopropanol, butanol, dimethylformamide,dimethylacetamide and dimethylsulfoxide.

The present invention also relates to improved processes for makingmirtazapine from crude mirtazapine comprising the steps of (a) heating amixture of crude mirtazapine and solvent; and (b) isolating mirtazapine.

In a preferred embodiment of the present invention, water is added tothe heated mixture of mirtazapine and solvent to facilitateprecipitation of mirtazapine.

In an additional embodiment of the present invention, preferred solventsare methanol, ethanol, isopropanol, acetone, toluene, and hexane andmixtures thereof.

In an additional embodiment of the present invention, preferred solventsare toluene, hexane, and methylene chloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparingpiperazine ring-containing compounds, such as mirtazapine, as describedin Scheme 2 below. The process of the present invention is advantageousover prior art processes due to, inter alia, the higher yield, smallernumber of steps in relation to the alternative methods, and minimizedraw material costs.

More particularly, the present invention relates to the process ofmaking mirtazapine from compounds of the formulae II, III and IV. In theprocess of the present invention the compound of formula II in Scheme 2above, wherein R¹ denotes hydroxymethyl, chloromethyl, bromomethyl oriodomethyl, and R² denotes amine, preferably —NH₂, is reacted with thecompound of formula III in Scheme 2 above, wherein R³ denotes chloro,fluoro, bromo or iodo, to form the compound of formula IV wherein R¹ isdefined as above.

In the process of the present invention, the compound of formula II isdissolved in a solvent such as methylene chloride. The compound offormula III is added to the solvent mixture and the resulting mixture isheated. Preferably the reaction mixture is heated to the refluxtemperature of the solvent. The mixture is heated to form the compoundof formula IV. Mirtazapine is then prepared by ring closure of thecompound of formula IV. Ring closure of the compound of formula IV maybe performed using a ring-closing reagent. Suitable ring closingreagents are dehydrating or dehydrohalogenating agents. Dehydrating ordehydrohalogenating agents that may be added to the reaction mixture forthis purpose include acids, such as sulfuric acid, concentrated sulfuricacid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoricacid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorustrioxide, phosphorus pentoxide and Lewis acids, such as aluminumchloride, ferric chloride, zinc chloride, tin chloride, titaniumchloride, boron trifluoride, antimony pentachloride and zirconiumtetrachloride.

Dehydrating agents that are particularly preferred are sulfuric acid andphosphorus derivatives, such as PPA and phosphorus oxychloride.Concentrated sulfuric acid most preferred. A particularly preferreddehydrohalogenating agent is aluminum chloride.

In a preferred embodiment of the present invention the compounds of theformulae II, III and IV are compounds of the formulae II′, III′ and IV′respectively as shown in Scheme 3 below. In an embodiment of the presentinvention, 2-amino-3-hydroxymethyl pyridine is reacted withN-methyl-1-phenyl-2,2′-iminodiethyl chloride to form1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine. In thepresent invention, 2-amino-3-hydroxymethyl pyridine (II′) is added to asolvent. Suitable solvents include 1,2-dichloroethane, methylenechloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide.N-Methyl-1-phenyl-2,2′-imidodiethyl-chloride (III′) is added to thesolvent mixture and the resulting mixture is heated. Preferably thereaction mixture is heated to the reflux temperature of the solvent. Themixture is heated until1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed andthe reaction is complete. A suitable time is about six to about 24hours. The 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine isthen converted to mirtazapine by ring closure.

The ring closure of1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is performedunder strongly dehydrating (R¹=OH) conditions, preferably at an elevatedtemperature. Suitable dehydrating agents, include acids, such assulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid,phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride,phosphorus trioxide and phosphorus pentoxide. Dehydrating agents thatare particularly preferred are sulfuric acid and phosphorus derivatives,such as PPA and phosphorus oxychloride. Concentrated sulfuric acid ismost preferred.

The present invention also provides new processes for making themirtazapine intermediate1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrile is(I) hydrolyzed by base using a new low mole to mole ratio of base to thenitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and (ii)hydrolyzed using short reaction times.

Where the present invention provides improved methods for making themirtazapine intermediate1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine, the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in amixture of water and organic solvent. Preferred organic solvents includepolar aprotic solvents and alcohols. Polar aprotic organic solvents suchas dimethylformamide, dimethylacetamide and dimethylsulfoxide and thelike are preferred. Preferred alcohols are methanol, ethanol, propanol,isopropanol, butanol and the like. A suitable amount of base, such aspotassium hydroxide or sodium hydroxide, is added to the reactionmixture. An amount of base, such as potassium hydroxide or sodiumhydroxide, of up to about 12 moles of base per mole of nitrile (forexample 12:1 KOH:nitrile) is preferred. Amounts of base, such aspotassium hydroxide, in the ratio of about 9 moles of potassiumhydroxide per one mole of nitrile (9:1 KOH:nitrile), to about 12 molesof potassium hydroxide per mole of nitrile (12:1 KOH:nitrile) arepreferred.

In the present invention, the mixture of the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, solvent and base isheated to at least about 130° C. Reaction temperatures of about 130° C.to about 150° are preferred. In an embodiment of the present invention,the reaction may be conducted under pressure to facilitate theattainment of high temperatures. A pressure of at least about 3atmospheres is preferred. Pressures of at least about 3 atmospheres toabout 4 atmospheres are more preferred. The reaction mixture is heateduntil the reaction is complete. The completion of the reaction may bemonitored by HPLC. The amount of time needed for the completion of thehydrolysis of the nitrile varies with the temperature of the reaction.Higher reaction temperatures generally require shorter reaction times,while lower reaction temperatures generally requires longer reactiontimes. While not limiting the reaction time of the present invention,preferred reaction times of the present invention may be from about 2hours to about 8 hours. Upon completion of the reaction, the pH of thereaction mixture is lowered, preferably to a pH of about 6 to about 7.Preferably the pH is lowered with hydrochloric acid. The mirtazapineintermediate, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine isisolated following washing and filtration of the reaction mixture.

In an additional embodiment of the present invention, the reactionmixture of the nitrile1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassiumhydroxide, is heated while using a minimum amount of water, such asabout 0.25-1 mL of water per gram of KOH, and small amounts of anaprotic solvent such as dimethylformamide, dimethylacetamide anddimethylsulfoxide, such as about 0.1 to 0.5 grams of aprotic solvent pergram of nitrile, under very concentrated conditions or almost neatconditions at atmospheric pressure. The mirtazapine intermediate,1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated followingwashing and filtration of the reaction mixture.

The new processes of the present invention for making the mirtazapineintermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine fromthe nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazinesignificantly reduce the quantity of potassium hydroxide used, from 25moles of potassium hydroxide per mole of the nitrile as in the '848patent, to about 12 moles or less of potassium hydroxide to one mole ofthe nitrile. The reduction in the amount of base needed considerablysimplifies the work-up of the reaction and minimizes environmentalproblems.

The present invention also provides new methods for making puremirtazapine by purifying crude mirtazapine by recrystallization. Uponthe ring closure of1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to formmirtazapine, the crude product, mirtazapine, is purified byrecrystallization.

It has been discovered that common solvents such as toluene or methylenechloride and solvent systems such as alcohol-water can be used in therecrystallization of crude mirtazapine. According to the presentinvention, crude mirtazapine is suspended in a suitable solvent.Preferred solvents include methanol, ethanol, isopropanol, and acetoneand mixtures thereof, or mixtures of one or more of those solvents withwater. Additional preferred solvents also include toluene, hexane, andmethylene chloride. Solvent mixtures of water and ethanol are morepreferred. Solvent mixtures of ratios of about 1:1 to about 1:4ethanol:water are preferred.

In the present invention, the suspension of crude mirtazapine andsolvent is heated to a suitable temperature. Suitable temperaturesinclude, for example, the reflux temperature of the solvent system beingused in any particular embodiment of the present invention. For example,in an embodiment of the present invention where toluene is the solvent,a temperature of about 110° C. is suitable. Purified mirtazapineprecipitates upon cooling of the reaction mixture. Filtration and dryingof the resulting precipitate yields purified, recrystallizedmirtazapine.

In a further example, crude mirtazapine is suspended in a solvent suchas ethanol, and the mixture is heated to reflux. Water is then addeddropwise and the solution is cooled to facilitate precipitation ofmirtazapine. The precipitate is purified by filtration, washing anddrying to yield purified mirtazapine. The crystallized mirtazapine maybe a water adduct thereby containing up to 3% water by weight (3% w/w).

The solvents and solvent systems of the present invention are suitablefor large scale reactions, and are more suitable for large scalereactions than ether or petrol ether 40-60. Additionally, thecrystallization yield can be substantially improved when using thesolvent system of the present invention.

Mirtazapine and mirtazapine intermediates,1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine each contain anasymmetric carbon atom, as a result of which separate optical isomersmay be prepared in addition to a racemic mixtures. Processes of thepresent invention include these optical isomers just as the racemicmixtures are included in the invention.

In accordance with the present invention, mirtazapine produced by theprocess of the present invention may be prepared as pharmaceuticalcompositions that are particularly useful for the treatment ofdepression. Such compositions comprise a therapeutically effectiveamount of mirtazapine with pharmaceutically acceptable carriers and/orexcipients known to one of skill in the art.

EXAMPLES

The following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope or spirit of the invention.

Example 1 Preparation of1-(3-Hydroxymethylpyridyl-2)-4-Methyl-2-Phenyl-Piperazine

In a 50 mL three-necked flask equipped with a mechanical stirrer, acondenser and a thermometer 1 g (0.008 mole) of 2-amino-3-hydroxymethylpyridine and 20 mL of 1,2-dichloroethane were charged. The mixing isstarted and to the suspension 2.8 g (0.012 mole) ofN-methyl-1-phenyl-2,2′-iminodiethyl-chloride are added. The reactionmixture is heated to reflux (˜80° C.) and maintained at this temperaturefor six hours.

After six hours the reaction mixture is cooled and the solvent(1,2-dichloroethane) is removed by dry distillation. A yellowish powderis obtained which contains 1.8 g 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (yield 80%). This powder can beused without additional purification for the preparation of mirtazapine.

Example 2 Preparation of Mirtazapine

In a 50 mL three-necked flask equipped with a mechanical stirrer, acondenser and a thermometer 1.8 g of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine are added to ˜5 mL ofconcentrated sulfuric acid that was previously cooled to 10° C. Theobtained solution is mixed at room temperature for 4 hours, then heatedfor one hour to about 50° to 60° C. After cooling, the reaction mass isadded to 25 g of ice under mixing and neutralized with a concentratedammonia solution or sodium hydroxide. The formed precipitate isseparated by filtration. The mother liquor is evaporated to drynessunder vacuum. Both the formed precipitate and the residue from themother liquor are each suspended in ˜20 mL of isopropanol. The combinedisopropanol extracts are evaporated to dryness. An oil is obtained whichcontains 1.35 g of mirtazapine (yield 80%).

Example 3 Preparation of Mirtazapine

1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) isadded to ˜5 mL of concentrated sulfuric acid. The resulting solution ismixed at 35° C. for 6 hours. After cooling, the reaction mixture isadded to 25 g of ice under mixing and basified with a concentratedammonia solution or sodium hydroxide solution to pH=10. The separatedprecipitate is extracted into methylene chloride and the extract isevaporated to dryness; 1.6 g of Mirtazapine is obtained (yield 95%).

Example 4 Preparation of1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine

1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) is dissolvedin 340 mL of ethanol and 34 mL of water. Potassium hydroxide flakes, 85%(113 g), are added and the reaction mixture is heated in an autoclave to140° C. The pressure increases to 3-4 atmospheres and the reactionmixture is maintained under pressure with mixing for 5 hours. After 5hours, the reaction mixture is cooled, the ethanol is removed from themixture by vacuum distillation, fresh water and toluene are added andthe 2 phases are separated. The water solution is neutralized withhydrochloric acid (HCl) to pH=6.5-7. At pH=6.5-7 the water is evaporatedand toluene is added. The inorganic salts are filtered and the toluenesolution is evaporated to dryness yielding 52 g of1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine (yield: 90%).

Example 5 Preparation of1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine

Potassium hydroxide (150 g of KOH flakes, 85%) and 75 mL of water and6.5 g of DMSO are added to1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and thereaction mixture is heated to 145-150° C. and mixed for 8 hours. After 8hours, the inorganic phase containing water and potassium hydroxide(KOH) is separated and the organic phase, containing mainly a productoil, is cooled. Fresh water and toluene are added and the two phases areseparated. The aqueous solution is neutralized with HCl to pH=6.5-7. AtpH=6.5-7, the water is evaporated and toluene is added. The inorganicsalts are filtered and the toluene solution is evaporated to drynessyielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine(yield: 90%).

Example 6 Recrystallization of Mirtazapine

Mirtazapine (20 g), obtained as in Examples 2 and 3, is suspended in 20mL of ethanol and heated to reflux. At reflux, 40 mL of water is addeddropwise to the solution over one hour followed by cooling to 10° C. Theresulting filter cake is washed with a solution of water:ethanol (2:1)and dried at 60° C. under a vacuum. Crystallized mirtazapine, 18 g, isobtained in 90% yield.

Table 1 sets forth a summary of additional experiments generallyfollowing procedures described above wherein the Yield % is the percentyield of mirtazapine crystals from crude mirtazapine and the Purity % isthe percent purity as compared to a mirtazapine standard.

TABLE 1 Purification of Crude Mirtazapine by Recrystallization Ratio ofsolvents Yield¹ Solvent system ml:ml/g Conditions % hexane 10 reflux 55toluene 3 reflux 32 toluene 2 refiux 53 acetone/water 6:25 25° C. 65ethanol/water 7:10 reflux 67 methanol/water 2.25:1.5 reflux 67ethanol/water 1.5:2 reflux 72 isopropyl/water 1.65:2 reflux 60acetone-water 3:2 reflux 53 ethanol/water 1:1.3 reflux 70 ethanol/water1.3:1.75 reflux 90.3 ethanol/water 1:4 reflux 100 ethanol/water 1.1:1.2reflux 87.8 ethanol/water 0.8:0.9 reflux 90 ethanol/water 0.8:1 reflux57 ethanol/water 0.6:0.7 reflux 89.1 ethanol/water 0.35:0.7 reflux 91.5ethanol/water 0.6:0.69 reflux 87 ethanol/water 2:2.8 reflux 95.6 ¹gmirtazapine crystals 100%/g mirtazapine crude 100%

Although certain presently preferred embodiments of the invention havebeen described herein, it will be apparent to those skilled in the artto which the invention pertains that variations and modifications of thedescribed embodiments may be made without departing from the spirit andscope of the invention. Accordingly, it is intended that the inventionbe limited only to the extent required by the appended claims and theapplicable rule of law.

We claim:
 1. A method for the preparation of mirtazapine, comprising thesteps of: (a) reacting a compound of the formula

with a compound of the formula

to form a compound of the formula

(b) admixing a ring closing reagent and the compound of the formula

to form mirtazapine wherein R¹ is selected from the group consisting ofhydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R² is amine;and R³ is selected from the group consisting of chloro, fluoro, bromoand iodo.
 2. The method of claim 1, wherein R¹ is hydroxymethyl, R² is—NH₂, and R³ is chloro.
 3. The method of claim 1, wherein said ringclosing reagent is selected from the group consisting of sulfuric acid,concentrated sulfur in acid, trifluoroacetic acid, phosphoric acid,polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide,phosphorus pentoxide, aluminum chloride, ferric chloride, zinc chloride,tin chloride, titanium chloride, boron trifluoride, antimonypentachloride and zirconium tetrachloride.
 4. The method of claim 2,wherein said ring closing reagent is sulfuric acid.
 5. A method for thepreparation of mirtazapine, comprising the steps of: (a) reacting2-amino-3-hydroxymethyl pyridine withN-methyl-1-phenyl-2,2′-iminodiethyl chloride to form1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine, and (b)adding a ring closing reagent to the1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to formmirtazapine.
 6. The method of claim 5, wherein said ring closing reagentis selected from the group consisting of sulfuric acid, concentratedsulfuric acid, trifluoroacetic acid, phosphoric acid, polyphosphoricacid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide,aluminum chloride, ferric chloride, zinc chloride, tin chloride,titanium chloride, boron trifluoride, antimony pentachloride andzirconium tetrachloride.
 7. The method of claim 5 wherein the ringclosing reagent is sulfuric acid.
 8. The method of claim 1, wherein thering closing reagent is either dehydrating agent or adehydrohalogenating agent.
 9. The method of claim 1, wherein the ringclosing reagent is selected from the group consisting of sulfuric acid,concentrated sulfuric acid, trifluoroacetic acid, phosphoric acid,polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide,phosphorus pentoxide, and Lewis acids.
 10. The method of claim 9,wherein the ring closing reagent is selected from the group consistingof sulfuric acid, polyphosphoric acid, phosphorus oxychloride, andaluminum chloride.
 11. The method of claim 10, wherein the ring closingreagent is sulfuric acid.
 12. The method of claim 5, wherein the ringclosing reagent is either a dehydrating agent or a dehydrohalogenatingagent.
 13. The method of claim 5, wherein the ring closing reagent isselected from the group consisting of sulfuric acid, concentratedsulfuric acid, trifluoroacetic acid, phosphoric acid, polyphosphoricacid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide,and Lewis acids.
 14. The method of claim 13, wherein the ring closingreagent is selected from the group consisting of sulfuric acid,polyphosphoric acid, phosphorus oxychloride, and aluminum chloride. 15.The method of claim 1, wherein the ring closing reagent and the compoundare admixed at a temperature ranging from about 10° C. to about 60° C.16. The method of claim 1, further comprising a cooling step after theadmixing step.
 17. The method of claim 16 wherein the cooling stepcomprises adding ice.
 18. The method of claim 1, further comprisingprecipitating the mirtazapine by adjusting the pH of the admixture toabout 7 to about
 10. 19. The method of claim 1, wherein R¹ ishydroxymethyl, wherein the ring closing reagent and the compound areadmixed at a temperature ranging from about 10° C. to about 60° C., andwherein the pH of the admixture is adjusted to about
 7. 20. The methodof claim 1, wherein R¹ is hydroxymethyl, wherein the ring closingreagent and the compound are admixed at about 10° C., and wherein the pHof the admixture is adjusted to about
 10. 21. The method of claim 1,further comprising a step of extracting the mirtazapine with a solvent.22. The method of claim 21, wherein the solvent is selected from thegroup consisting of methanol, ethanol, isopropanol, acetone, mixturesthereof, toluene, hexane, methylene chloride, and mixtures thereof. 23.The method of claim 22, wherein the solvent is selected from the groupconsisting of isopropanol and methylene chloride.
 24. The method ofclaim 16, further comprising heating the admixture prior to the coolingstep.